Targeting the autocrine loop of cardiac myofibroblasts to fight fibrosis

Cardiac fibrosis (CF) remains a major challenge in the field of cardiac repair, as there is no preventive measures or therapy to revert cardiac scarring. We asked what the organizing principles in CF development, and what are the molecular entities that drive this pathology. Recently, we have established an in-silico model for a minimal macrophage-myofibroblast cell-circuit that orchestrates tissue repair and fibrosis. We set out to explore this cell-circuit in the setting of myocardial infarction (MI) that yields sustained fibrosis. By employing unbiased, high-throughput methods and mathematical modelling we revealed that when regenerative capacity exists, as in neonatal mice, both macrophages and myofibroblasts trajectories first rise and then return to baseline levels. In contrast, in a non-regenerative model of MI in adult mice, macrophages and myofibroblasts rise together for a prolonged period of time, followed by a drop in macrophages to pre-injury levels. This resembles cold fibrosis, a stable point in which myofibroblasts are self-sustained. Under cold-fibrosis, macrophages regain their homeostatic functions, while cardiac-fibroblasts acquire a de-novo pro-fibrotic phenotype which is sustained within the mature scar. In-silico simulation revealed myofibroblasts growth rate, controlled by an autocrine loop, as the most prominent factor governing the regenerative window. NicheNet analysis revealed Timp1 as a novel cardiac myofibroblasts autocrine growth factor, promoting CF. In-vivo neutralization of TIMP1 reduced CF following MI in adult mice. These findings suggest a key cell-circuit in CF development, centered on a myofibroblasts autocrine signaling loop. Such insights may lead to development of an effective therapy for CF.